Immunological Development and Cardiovascular Function Are Normal in Annexin VI Null Mutant Mice

Abstract

Annexins are calcium-binding proteins of unknown function but which are implicated in important cellular processes, including anticoagulation, ion flux regulation, calcium homeostasis, and endocytosis. To gain insight into the function of annexin VI, we performed targeted disruption of its gene in mice. Matings between heterozygous mice produced offspring with a normal Mendelian pattern of inheritance, indicating that the loss of annexin VI did not interfere with viability in utero. Mice lacking annexin VI reached sexual maturity at the same age as their normal littermates, and both males and females were fertile. Because of interest in the role of annexin VI in cardiovascular function, we examined heart rate and blood pressure in knockout and wild-type mice and found these to be identical in the two groups. Similarly, the cardiovascular responses of both sets of mice to septic shock were indistinguishable. We also examined components of the immune system and found no differences in thymic, splenic, or bone marrow lymphocyte levels between knockout and wild-type mice. This is the first study of annexin knockout mice, and the lack of a clear phenotype has broad implications for current views of annexin function.

Identification of Annexin VI as a Ca2+-sensitive CRHSP-28-binding Protein in Pancreatic Acinar Cells

“…Annexin VI has been implicated as an important regulatory component of clathrin-mediated endocytosis (15)(16)(17)28), although the primary significance of the protein in this process remains unclear (29). Lin et al (28) used an in vitro system to demonstrate that annexin VI is required for the Ca 2ϩ -and ATP-dependent budding of clathrin-coated pits from membranes.…”

Annexins – insights from knockout mice

“…Alternatively, compensatory mechanisms were proposed to alleviate the loss of AnxA6 in vivo. However, while several annexins were found to be upregulated in the AnxA1 KO mice (Hannon et al, 2003), AnxA1, A2 and A5 protein levels in the heart, liver and spleen of the AnxA6 -/-mice remained unchanged (Hawkins et al, 1999). This indicated that at least these annexins were not upregulated to compensate for the loss of AnxA6 in these organs.…”

“…However, depending on the cell type analysed, several non-conventional secretion pathways seem to contribute to the cellular export of AnxA1 (Gerke et al, 2005;Perretti and D'Acquisto, 2009;Gavins and Hickey, 2012). After the successful generation of viable AnxA6 and AnxA7 KO strains (Hawkins et al, 1999;Herr et al, 2001; see below), Flower, Hannon and colleagues generated the AnxA1 KO mice (AnxA1 -/-) to provide proof-of-principle in vivo that AnxA1 confers glucocorticoid-dependent activation of innate immune cells to limit pro-inflammatory response (Hannon et al, 2003) (Table 2). AnxA1 KO mice were healthy and bred normally without obvious physical or behavioral difference compared to control animals.…”

“…Reduced amplitude of Ca 2+ transients, impaired contractility and cardiomyopathy suggested that elevated AnxA6 levels in the heart interfered with Ca 2+ homeostasis, possibly through regulation of membrane-associated ion pumps and/or exchangers of cardiomyocytes. However, despite these encouraging first insights, the generation of the AnxA6 KO mice by Moss and coworkers resulted in animals lacking a clear phenotype (Hawkins et al, 1999) (Table 6). Loss of the AnxA6 gene was not associated with noticeable morphological changes and did not interfere with overall viability and fertility.…”

Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity

“…In a prostate cancer model, downregulation of annexin A6 was observed during progression from a benign to a malignant state (K Rasiah and R Sutherland, personal communication); these findings suggest a tumour suppressor role for annexin A6 in malignant progression. However, despite reduced levels in cancer models, annexin A6 knockoutmice appear normal and do not develop spontaneous tumours (Hawkins et al, 1999;TG, unpublished results). These findings are similar to results for annexin A2 and A7, which are linked to cell growth and transformation (Checuti et al, 2001;Srivastava et al, 2001;Liu et al, 2003), but annexin A2 and A7 null animals do not develop tumours (Herr et al, 2001;Ling et al, 2004), suggesting that some annexins could functionally replace one another (reviewed in Gerke and Moss, 2002).…”